Liposomes are well established nanoparticles that can enhance the efficacy of therapeutically active drugs by improving the plasma distribution and pharmacokinetics of the drugs over non-encapsulated forms (e.g., Weinstein, Liposomes: From Biophysics to Therapeutics, (Ostro, M. J., ed.), Marcel Dekker, Inc., N.Y., pp. 277-338, (1987). For example, Vincristine Sulfate Liposome Injection (VSLI) is a liposome formulation of the anti-cancer therapeutic vincristine sulfate encapsulated in sphingomyelin-cholesterol liposomes, which provides greater efficacy than standard vincristine sulfate injection USP (VSI). Clinical trials have also shown that VSLI facilitates dose intensification by significantly extending vincristine's circulation half-life compared to non-encapsulated vincristine. The liposome provides the mechanism for delayed drug release and the liposome size allow the drug to accumulate in cancer tissues by extravasation (Webb et al., Cancer Chemother. Pharmacol 42:461-470, 1998; Shan et al., Cancer Chemother. Pharmacol 58:245-255, 2006). These features translate into improved clinical benefit over the standard VSI.
Consistency of product quality and performance is a key parameter of all drug products. During development and optimization of liposome drug formulations, a variety of physical and chemical tests commonly performed on liposome drug products (e.g., solubility, particle size, osmolality, homogeneity) have historically provided reasonable evidence of consistent performance. However, alterations in formulation composition, manufacturing process, equipment and batch sizes may require studies in human healthy volunteers, increasing the time and cost of the getting the drug on the market.
More recently, in vitro release testing has been employed as a means to evaluate release characteristics that reflect in vivo bioavailability. In vitro drug release testing measures, the release of the active ingredient from the drug product in controlled laboratory environment and should simulate the physiological environment of human plasma. It involves subjecting the dosage form to a set of conditions that will induce drug release and quantitating the amount of drug released under those conditions. During drug development, the test can be used to assess differences in formulations, to predict the timeframe of active ingredient release, and in vivo behavior. As a tool for quality control, the test can be used to assess conformance of a batch to pre-determined criteria at time of manufacture and to assess the long-term stability and release of the active ingredient. In vitro release assays can also assist in quality control for certain scale-up and post-approval changes (SUPAC).
One of the key challenges, however, is developing an in vitro drug release assay that discriminates between different liposome compositions and physiochemical characteristics and how they affect in vivo drug profiles. Although human plasma has been employed as a medium for in vitro release, as a means to simulate the in vivo environment, the practical difficulties of biosafety and inherent lot-to-lot variability of plasma makes this an unacceptable option for routine product testing. Thus, there remains a need for reliable in vitro methods that provide a means for assuring that each batch of the same liposome product will have drug release characteristics that are substantially identical.